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1115 Pharmacology and Pharmaceutical Sciences, Pharmacology & Pharmacy, 3214 Pharmacology and pharmaceutical sciences

Abstract:

Purpose. To investigate the effects of sub-chronic oral treatment of rats with the 5HT4 agonist prucalopride (PRU) on the elimination and biliary excretion of thyroxine (T4) and its glucuronide (T4G). Methods. Male Hannover Wistar rats were treated by oral gavage either for 6 months with control vehicle solution or with PRU at 80 mg/kg/day, or for 7 days with the liver enzyme inducer phenobarbital (PB) as positive control. At the end of the treatment, animals were implanted with a bile cannula under isoflurane anesthesia, allowed to recover, and subsequently dosed with an intravenous tracer dose of 3H-T4 (5 &[micro]g/kg; ~ 40 &[micro]Ci/kg). Bile was collected for 24 hr and analyzed by liquid scintillation counting and radio-HPLC to determine concentrations of total radioactivity and of T4 and T4G. Biliary excretion of T4 and T4G was calculated and expressed as average % (&[plusmn] sem; n=13-15) of the administered dose radioactivity. Results. The cumulative excretion of total radioactivity in the bile was increased significantly from 31.1 &[plusmn] 0.8 % in vehicle-treated rats to 39.4 &[plusmn] 1.4 % in PRU-treated rats and to 48.4 &[plusmn] 1.6 % in PB-treated rats. The cumulative biliary excretion of T4 and T4G in vehicle-treated rats amounted to 1.7 &[plusmn] 0.1 % and 12.8 &[plusmn] 0.7 % of the dose, respectively. In animals treated with PRU at 80 mg/kg/day, T4 and T4G biliary excretion increased significantly to 2.5 &[plusmn] 0.2 % and 18.8 &[plusmn] 1.5 %, respectively. In animals treated with the positive control agent PB, T4 biliary excretion remained unchanged (2.0 &[plusmn] 0.2 %), while the biliary excretion of T4G increased significantly to 22.7 &[plusmn] 1.6 %. Conclusion. These results indicate enhanced hepatic elimination and biliary excretion of T4 and T4G when rats are treated sub-chronically with high doses of the 5HT4 agonist prucalopride. The mechanism behind this observation is currently under investigation.